The etiology and pathogenesis of rheumatoid arthritis (RA) remain obscure despite intense investigation. Chemokines play a critical role in attracting and retaining leukocytes in the inflamed joints. However, the precise mechanism for cell positioning in the joints is unclear. The long-term goal of this project is to understand the mechanism of cell trafficking and inflammatory responses in nonlymphoid tissues in the settings of autoimmune diseases. Recently we have found that CXCL16, a newly identified chemokine, and its receptor, CXCR6, are highly expressed in the joints of mice with collagen-induced arthritis (CIA), an animal model of RA. CXCL16 is the second member of the chemokine family with a transmembrane domain. The receptor-bearing cells are mainly Th1 cells, display extralymphoid tissue homing potential and are enriched in inflamed synovial fluid of RA patients. Treatment of mice with CXCL16-Ig fusion protein significantly ameliorates CIA. Thus, we hypothesize that CXCL16/CXCR6 play an important role in the pathogenesis of autoimmune arthritis. This project will focus on the mechanisms that regulate CXCL16/CXCR6 expression and the contribution of CXCL16/CXCR6 to the initiation and progression of CIA. Chemokines that are preferentially expressed in Th1-mediated inflammatory disorders like RA, such as CXCR3 and CCR5, will also be investigated during the course of CIA as comparative studies to further elucidate the role of CXCL16/CXCR6 in the pathogenesis of CIA. In addition, we hypothesize that CXCL16-CXCR6 may mediate interactions among T cell, B cells, macrophages and other cells in the affected sites because of the unique structure CXCL16 as a membrane chemokine and its expression pattern. The role of CXCL16/CXCR6 in mediating T cell-antigen presenting cells will be studied. Aside from enhancing our understanding of leukocyte migration in rheumatoid joints, these studies are expected to provide important information regarding chemokine functions in regulating activation and differentiation of lymphocytes and macrophages during inflammatory responses. The study will also provide insights into new targets for designing anti-inflammatory agents in autoimmune arthritis and other autoimmune diseases.